Abstract Using a novel ex vivo stimulation method allowing measurement of brain responses to insulin, our research group established in 2012 a very common and profound abnormality in AD dementia cases closely associated with accelerated cognitive decline. That abnormality is brain insulin resistance, which can be induced by many early pathogenic factors in AD (including systemic insulin resistance) and can in turn cause or exacerbate many of its later pathologic features and cognitive deficits. Brain insulin resistance thus appears to be a nodal abnormality in AD, one whose alleviation may slow disease progression by exerting therapeutic effects on a broad spectrum of pathologies and thereby slow cognitive decline in AD. If so, it may be possible to treat AD by reducing brain insulin resistance. Among the most promising agents available for reducing brain insulin resistance are drugs in a relatively new class of antidiabetics known as incretin receptor agonists (IRAs), which are already known to reduce systemic insulin resistance. IRAs activate one or both of the 2 major incretin receptors: glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR). At least 3 IRAs cross the blood- brain barrier, namely two GLP-1R agonists (exendin-4 and liraglutide) and a recently developed dual GLP- 1R/GIPR agonist (i.e., a dual IRA). Administered outside the CNS, then, these IRAs could reduce both systemic and brain insulin resistance, in the latter case by activating GLP-1R and GIPR found in especially vulnerable areas of AD cases, including the neocortex and hippocampal formation. Our preliminary data show that IRAs applied ex vivo to the hippocampal formation from mild cognitive impairment (MCI) cases markedly reduce insulin resistance in that brain structure and that the dual IRA has this effect even in advanced AD dementia (ADd) cases. Given these striking findings, we propose a preclinical evaluation of the hypothesis that AD can be treated by reducing brain insulin resistance with IRAs. Our approach is innovative in testing candidate AD therapeutics for their physiological effects on brain tissue from both an animal model of AD and from actual AD (and MCI) cases. Our candidate therapeutics (exendin-4, liraglutide, and a dual IRA) will be tested on 3 target brain areas in AD (lateral prefrontal cortex, posterior parietal cortex, and hippocampal formation) from (a) wild-type and APP/PS1 mice and (b) normal, MCI, and ADd cases. Aim 1 will determine the relative efficacy and pharmacokinetics of the 3 IRA candidates in reducing brain insulin resistance and their ability to reach the target brain areas via their normal subcutaneous route of administration. Aim 2 will test molecular mechanisms by which these drugs reduce brain insulin resistance. Aim 3 will test if IRA-induced reductions in brain insulin resistance are closely associated with reductions in a wide range of AD-related pathologies (e.g., elevated A?, increased phosphorylated tau, decreased cerebral glucose utilization) and spatial memory deficits.